Nearly 60 million Americans are estimated to suffer from systemic hypertension, and the hallmark finding of this disease is an abnormally high peripheral vascular resistance. Additionally, vasospasm is a finding in some forms of coronary, cerebral and systemic arterial occlusions and also can occur during or after angioplasty to relieve vascular stenoses. New therapeutic approaches are needed to reduce the anomalous vascular tone. For example, only about one-third of patients with essential hypertension (i.e., hypertension of unknown etiology) are successfully treated by standard antihypertensive drugs, and most of these patients require daily, multi-drug therapy to achieve blood pressure reduction, which may lead to one or more side effects.
High-conductance voltage- and calcium-activated potassium channels, named “BK channels” because of their big unitary conductances (150 to 300 pS), are expressed in all vascular beds. The opening of these channels mediates a hyperpolarizing potassium current that buffers contraction of vascular smooth muscle cells (VSMCs) in the arterial wall, resulting in vasodilation of small arteries and arterioles. The α subunit of the BK channel forms the ion-conducting pore, and appears to arise from a single gene family, although phenotypic diversity may be generated by a high level of alternative splicing of the common primary transcript. The BK channel complex also includes a β subunit that increases the sensitivity of the α subunit to intracellular calcium, thereby enhancing its activation level. Deletion of the subunit in KO mice to create poorly functional BK channels results in a blood pressure elevation of approximately 20 mm Hg.
During vascular activation caused by vasoconstrictor stimuli, membrane depolarization and the associated rise in cytosolic calcium act synergistically to further open BK channels. Thus, the BK channels buffer VSMC excitation and prevent abnormal arterial contraction by exerting a vasodilator influence. However, this vasodilator influence cannot fully dampen anomalous vasoconstriction under some conditions, including local vasospasm and during pulmonary or systemic hypertension in which an elevated arterial tone persists despite the activation of compensatory mechanisms. Under these conditions, therapeutic interventions are required to restore normal levels of vascular tone.
A unique vasodilator therapy comprising the long-term expression of a potent endogenous vasodilator protein in smooth muscle cells has clear advantages over standard antihypertensive drugs in terms of cost, convenience, and tissue and target specificity. Such a method may provide long-term vasodilation with few side effects compared to standard vasodilator and antihypertensive therapies.
The long-term delivery of BK channels to VSMCs using a smooth muscle-specific promoter provides at least two important advantages. First, its hyperpolarizing influence may limit further increases in vascular resistance and blood pressure during the pathogenesis of hypertension. Second, a higher density of BK channels may prevent or alleviate anomalous vasoconstriction and vasospasm in a single vessel or in a vessel network.